The overall objective of this U01 application is to provide support for consortia of institutions to perform Phase I and II clinical trials of new chemotherapeutic and biologic agents in patients with primary central nervous system (CNS) tumors and to perform ancillary laboratory studies with potential clinical implications. The Brain Tumor Center at the Dana- Farber Cancer Institute and the Brigham and Women's Hospital has a large an expanding patient population and commitment ot clinical and laboratory research of primary brain tumors. As part of the "National CNS Tumor Consortium" our general goals are the following: 1). To define the toxicities of new anti-tumor agents (Phase I) and determine a treatment regimen suitable for evaluation of those agents in Phase II studies of patients with primary CNS malignancies; 2). To define the pharmacokinetics (absorption, distribution, metabolism, and elimination) and pharmacodynamics (effects at the biochemical and molecular levels) of these agents; 30. To conduct phase II trials of new anti-cancer agents in order to determine the activity in patients with primary CNS tumors; and 4). To obtain tumor and other patient specimens for laboratory studies relevant to the clinical trials. The scope of this institution's program will be to perform Phase I and II trials of new cytotoxic drugs, biologic response modifiers (particularly interferons), and anti-angiogenesis agents and to perform the pharmacokinetic trials for the consortium. In addition to the pharmacokinetic analyses, laboratory studies will focus on potentially clinical relevant biological endpoints to therapy including specific gene expression, changes in signal transduction pathways, modulation of immune function, and inhibition of angiogenesis depending on the specific drug being tested. Since the specific agents to be studied over the next four years are unknown at this time, we have chosen two agents as examples: 1). TNP-470, a new powerful inhibitor or angiogenesis and whose development was the result of fundamental work on angiogenesis in our laboratories; and 2). BG9015, the first fully glycosylated non-mutated recombinant human beta- interferon. Through these examples we hope to be able to demonstrate our ability to design appropriate clinical trials and to evaluate new agents directed against novel biologic targets (i.e. angiogenesis, immune- regulatory) and to develop correlative laboratory studies that may ultimately have significant clinical implications. The specific aims of this proposal are therefor: 1.) To conduct a Phase I pharmacokinetic and pharmacodynamic trial of the angiogenic inhibitor TNP-470 in patients with recurrent high-grade astrocytomas; and 2.) To conduct a Phase I pharmacokinetic and pharmacodynamic trial of a new beta-interferon, BG9015, in patients with recurrent malignant gliomas.